Sinomenine derivatives and processes for their synthesis

ABSTRACT

The invention generally provides processes and intermediate compounds useful for the production of sinomenine derivatives. In particular, the process may encompass synthetic routes for the production of (+)-sinomenine derivatives and their intermediates.

CROSS-REFERENCE TO RELATED APPLICATION

This patent application is a divisional application of U.S. patentapplication Ser. No. 12/316,846 (filed on Dec. 17, 2008), which claimspriority from Provisional Patent Application Ser. No. 61/014,099 (filedon Dec. 17, 2007), the contents of which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to processes and intermediatecompounds useful for the production of sinomenine derivatives.

BACKGROUND OF THE INVENTION

Sinomenine, an alkaloid isolated from the root of Sinomenium acutum, hasbeen reported to possess anti-inflammatory, analgesic, blood pressurelowering, and anti-arrhythmia activities. Both the isolated molecule andthe S. acutum plant have been used clinically in China for the treatmentof rheumatoid arthritis. Although sinomenine relieves the symptoms ofrheumatoid arthritis, it has some undesirable side effects. It ispossible, therefore, that compounds with structures related tosinomenine would be more effective clinically, while having feweruntoward effects.

SUMMARY OF THE INVENTION

One aspect of the invention encompasses a compound comprising Formula(I):

wherein:

R¹ is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl;

R² and R³ are independently selected from the group consisting ofhydrogen, halogen, OH, NH₂, CN, hydrocarbyl, and substitutedhydrocarbyl;

R⁴ is selected from the group consisting of hydrogen, halogen, NH₂, CN,hydrocarbyl, substituted hydrocarbyl, and OR^(4a);

R^(4a) is selected from the group consisting of hydrogen and a bond thatforms part of an ether-containing ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁵ and R⁶ together may form a group selected from the group consistingof ═O, ═NOH, ═S, ═CHR^(5a), and —O(CH₂)₂O—;

R^(5a) is selected from the group consisting of hydrogen, halogen,hydrocarbyl, and substituted hydrocarbyl;

R⁷ is selected from the group consisting of hydrogen and OR¹³;

R^(7a) is selected from the group consisting of hydrocarbyl andsubstituted hydrocarbyl;

R⁸ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁹ and R¹⁰ together may form a group selected from the group consistingof ═O and ═S;

R¹¹ and R¹² are independently selected from the group consisting ofhydrogen, OH, halogen, hydrocarbyl, and substituted hydrocarbyl;

Y is selected n is from the group consisting of alkyl, substitutedalkyl, carbonyl, and alkyl carbonyl;

m is an integer from 0 to 8; and

----- is a single bond or a double bond.

An additional aspect of the invention encompasses a process forpreparing a compound comprising Formula 3. The process comprisescontacting a compound comprising Formula 2 with a compound selected fromthe group consisting of vinyl chloroformate and 1-chloroethylchloroformate, followed by hydrolysis of the reaction mixture in thepresence of a proton donor or a proton acceptor to form the compoundcomprising Formula 3 according to the reaction scheme:

wherein

R¹, R², R³, and R⁴ are independently selected from the group consistingof hydrogen, halogen, OH, NH₂, CN, hydrocarbyl, and substitutedhydrocarbyl;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁵ and R⁶ together may form a group selected from the group consistingof ═O, ═NOH, ═S, ═CHR^(5a), and —O(CH₂)₂O—; and

R^(5a) is selected from the group consisting of hydrogen, halogen,hydrocarbyl, and substituted hydrocarbyl; and

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁸ and R⁹ together may form a group selected from the group consistingof ═O and ═S.

A further aspect of the invention provides a process for preparing acompound comprising Formula 4. The process comprises contacting acompound having Formula 3 with a compound selected from the groupconsisting of R⁷YX and R⁷Y to form the compound comprising Formula 4according to the reaction scheme:

wherein

R¹, R², R³, and R⁴ are independently selected from the group consistingof hydrogen, halogen, OH, NH₂, CN, hydrocarbyl, and substitutedhydrocarbyl;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁵ and R⁶ together may form a group selected from the group consistingof ═O, ═NOH, ═S, ═CHR^(5a), and —O(CH₂)₂O—; and

R^(5a) is selected from the group consisting of hydrogen, halogen,hydrocarbyl, and substituted hydrocarbyl.

R⁷ is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl;

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁸ and R⁹ together may form a group selected from the group consistingof ═O and ═S;

X is halogen; and

Y is selected n is from the group consisting of alkyl, substitutedalkyl, carbonyl, and alkyl carbonyl.

An additional aspect of the invention provides a process for preparing acompound comprising Formula 5. The process comprises contacting acompound having Formula 4a with X to form the compound comprisingFormula 5 according to the reaction scheme:

wherein

R¹, R², R³, and R⁴ are independently selected from the group consistingof hydrogen, halogen, OH, NH₂, CN, hydrocarbyl, and substitutedhydrocarbyl;

R⁷ is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl;

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁸ and R⁹ together may form a group selected from the group consistingof ═O and ═S;

X is halogen; and

Y is selected n is from the group consisting of alkyl, substitutedalkyl, carbonyl, and alkyl carbonyl.

A further aspect of the invention provides a process for preparing acompound comprising Formula 6. The process comprises contacting acompound having Formula 5a with a proton acceptor to form the compoundcomprising Formula 6 according to the reaction scheme:

wherein

R¹, R², and R³ are independently selected from the group consisting ofhydrogen, halogen, OH, NH₂, CN, hydrocarbyl, and substitutedhydrocarbyl;

R⁴ is selected from the group consisting of OH and NH₂;

R⁷ is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl;

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁸ and R⁹ together may form a group selected from the group consistingof ═O and ═S; and

X is halogen;

Y is selected from the group consisting of alkyl, substituted alkyl,carbonyl, and alkyl carbonyl; and

Z is selected from the group consisting of {—}O{—} and {—}NH{—}.

Another aspect of the invention encompasses a process for preparing acompound comprising Formula 7. The process comprises contacting acompound having Formula 6 with a scavenger and a proton donor to formthe compound comprising Formula 7 according to the reaction scheme:

wherein

R¹, R², and R³ are independently selected from the group consisting ofhydrogen, halogen, OH, NH₂, CN, hydrocarbyl, and substitutedhydrocarbyl;

R⁷ is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl;

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁸ and R⁹ together may form a group selected from the group consistingof ═O and ═S;

Y is selected from the group consisting of alkyl, substituted alkyl,carbonyl, and alkyl carbonyl; and

Z is selected from the group consisting of {—}O{—} and {—}NH{—}.

An additional aspect of the invention encompasses a process forpreparation of compound 7 according to the following reaction scheme:

wherein:

R¹ is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl;

R² and R³ are independently selected from the group consisting ofhydrogen, halogen, OH, NH₂, CN, hydrocarbyl, and substitutedhydrocarbyl;

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁴ and R⁵ together may form a group selected from the group consistingof ═O, ═NOH, ═S, ═CHR^(5a), and —O(CH₂)₂O—;

R^(5a) is selected from the group consisting of hydrogen, halogen,hydrocarbyl, and substituted hydrocarbyl;

R⁶ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁸ and R⁹ together may form a group selected from the group consistingof ═O and ═S;

X is halogen;

Y is selected n is from the group consisting of alkyl, substitutedalkyl, carbonyl, and alkyl carbonyl; and

Z is selected from the group consisting of {—}O{—} and {—}NH{—}.

Other aspects and iterations of the invention are described in moredetail below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides processes and intermediate compounds forproducing sinomenine derivatives. These sinomenine derivatives may bemore specific, more efficacious, and/or more potent than sinomenine.Additionally, these sinomenine derivatives may have fewer side effectsthan sinomenine.

(I) Sinomenine Derivatives

The sinomenine derivatives and intermediates that may be used to makesinomenine derivatives generally comprise formula (I), (Ia), (Ib), and(Ic), as described below.

(a) Compounds Having Formula (I)

In one embodiment of the invention, the sinomenine derivative comprisesformula (I):

wherein:

R¹ is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl;

R² and R³ are independently selected from the group consisting ofhydrogen, halogen, OH, NH₂, CN, hydrocarbyl, and substitutedhydrocarbyl;

R⁴ is selected from the group consisting of hydrogen, halogen, NH₂, CN,hydrocarbyl, substituted hydrocarbyl, and OR^(4a);

R^(4a) is selected from the group consisting of hydrogen and a bond thatforms part of an ether-containing ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁵ and R⁶ together may form a group selected from the group consistingof ═O, ═NOH, ═S, ═CHR^(5a), and —O(CH₂)₂O—;

R^(5a) is selected from the group consisting of hydrogen, halogen,hydrocarbyl, and substituted hydrocarbyl;

R⁷ is selected from the group consisting of hydrogen and OR^(7a);

R^(7a) is selected from the group consisting of hydrocarbyl andsubstituted hydrocarbyl;

R⁸ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁹ and R¹⁰ together may form a group selected from the group consistingof ═O and ═S;

R¹¹ and R¹² are independently selected from the group consisting ofhydrogen, OH, halogen, hydrocarbyl, and substituted hydrocarbyl;

Y is selected from the group consisting of alkyl, substituted alkyl,carbonyl, and alkyl carbonyl;

m is an integer from 0 to 8; and

----- is a single bond or a double bond.

In another embodiment, the compound comprises Formula (I), wherein:

R¹ is selected from the group consisting of an alkyl group having from 1to 8 carbon atoms, a vinyl group, an aryl group, cyclopropyl,cyclobutyl, {—}CH(CF₃)₂, {—}CH(CH₃)CF₃, {—}CH═CF₂ and {—}CH₂CF₃;

R² is selected from the group consisting of hydrogen and halogen;

R³ is hydrogen;

R⁴ is OR^(4a);

R^(4a) is selected from the group consisting of hydrogen and a bond thatforms part of an ether-containing ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, and NH₂, wherein R⁵ and R⁶ together may form ═O;

R⁷ is as defined above;

R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each hydrogen;

Y is selected from the group consisting of {—}CH₂{—} and {—}CO{—}; and

m is 0.

In a preferred alternative of this embodiment, R⁷ is OR^(7a) and R^(7a)is selected from the group consisting of alkyl and substituted alkylhaving from 1 to 8 carbon atoms. In an exemplary iteration of thisalternative, R^(7a) is methyl.

In a further embodiment, the compound comprises Formula (I), wherein:

R¹ is cyclopropyl;

R² is halogen;

R³ is hydrogen;

R⁴ is OR^(4a); R^(4a) is selected from the group consisting of hydrogenand a bond that forms part of an ether-containing ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, and NH₂, wherein R⁵ and R⁶ together may form ═O;

R⁷ is selected from the group consisting of hydrogen and OR^(7a);

R^(7a) is selected from the group consisting of alkyl and substitutedalkyl having from 1 to 8 carbon atoms;

R⁸, R⁹, R¹⁰, R¹¹, and R¹² are each hydrogen;

Y is selected from the group consisting of {—}CH₂{—} and {—}CO{—}; and

m is 0.

For this embodiment, preferably, R² is bromide or chloride. In anexemplary alternative of this embodiment, R⁷ is OR^(7a) and R^(7a) ismethyl.

(b) Compounds Having Formula (Ia)

In a further embodiment of the invention, the compound comprises Formula(Ia):

wherein:

R² is selected from the group consisting of hydrogen, halogen, OH, NH₂,CN, hydrocarbyl, and substituted hydrocarbyl;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁵ and R⁶ together may form a group selected from the group consistingof ═O, ═NOH, ═S, ═CHR^(5a), and —O(CH₂)₂O—;

R^(5a) is selected from the group consisting of hydrogen, halogen,hydrocarbyl, and substituted hydrocarbyl;

R⁷ is selected from the group consisting of hydrogen and OR^(7a);

R^(7a) is selected from the group consisting of hydrocarbyl andsubstituted hydrocarbyl;

R⁸ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R⁸ and R¹⁰ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁹ and R¹⁰ together may form a group selected from the group consistingof ═O and ═S;

Z is selected from the group consisting of {—}O{—}, {—}S{—}, and{—}NH{—}; and

----- is a single bond or a double bond.

In an alternate embodiment, the compound comprises Formula (Ia),wherein:

R² is selected from the group consisting of halogen and hydrogen;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, and NH₂ wherein R⁵ and R⁶ together may form ═O;

R⁷ is OR^(7a) and R^(7a) is selected from the group consisting of alkyland substituted alkyl having from 1 to 8 carbon atoms;

R⁸, R⁹, and R¹⁰ are each hydrogen; and

Z is oxygen.

In a preferred alternative of this embodiment, R² is halogen and R^(7a)is methyl. Preferably, the halogen is bromide or chloride.

(c) Compounds Having Formula (Ib)

In still another embodiment, the compound comprises Formula (Ib):

wherein:

R² is selected from the group consisting of hydrogen, halogen, OH, NH₂,CN, hydrocarbyl, and substituted hydrocarbyl;

R⁴ is selected from the group consisting of hydrogen, halogen, NH₂, CN,hydrocarbyl, substituted hydrocarbyl, and OR^(4a).

R^(4a) is selected from the group consisting of hydrogen and a bond thatforms part of an ether-containing ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁵ and R⁶ together may form a group selected from the group consistingof ═O, ═NOH, ═S, ═CHR^(5a), and —O(CH₂)₂O—;

R^(5a) is selected from the group consisting of hydrogen, halogen,hydrocarbyl, and substituted hydrocarbyl;

R⁷ is selected from the group consisting of hydrogen and OR^(7a);

R^(7a) is selected from the group consisting of hydrocarbyl andsubstituted hydrocarbyl; and

----- is a single bond or a double bond.

In another embodiment, the compound comprises Formula (Ib), wherein:

R² is selected from the group consisting of hydrogen and halogen;

R⁴ is OR^(4a);

R^(4a) is selected from the group consisting of hydrogen and a bond thatforms part of an ether-containing ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, and NH₂ wherein R⁵ and R⁶ together may form ═O; and

R⁷ is OR^(7a) and R^(7a) is selected from the group consisting of alkyland substituted alkyl having from 1 to 8 carbon atoms.

In an exemplary alternative of this embodiment, R² is halogen and R^(7a)is methyl. Preferably, the halogen is bromide or chloride.

(d) Compounds Having Formula (Ic)

In yet another embodiment, the compound comprises Formula (Ic):

wherein:

R² is selected from the group consisting of hydrogen, halogen, OH, NH₂,CN, hydrocarbyl, and substituted hydrocarbyl;

R⁴ is selected from the group consisting of hydrogen, halogen, NH₂, CN,hydrocarbyl, substituted hydrocarbyl, and OR^(4a);

R^(4a) is selected from the group consisting of hydrogen and a bond thatforms part of an ether-containing ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁵ and R⁶ together may form a group selected from the group consistingof ═O, ═NOH, ═S, ═CHR^(5a), and —O(CH₂)₂O—; and

R^(5a) is selected from the group consisting of hydrogen, halogen,hydrocarbyl, and substituted hydrocarbyl.

In another alternate embodiment, the compound comprises Formula (Ic),wherein:

R² is selected from the group consisting of hydrogen and halogen;

R⁴ is OR^(4a);

R^(4a) is selected from the group consisting of hydrogen and a bond thatforms part of an ether-containing ring; and

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, OH, and NH₂, wherein R⁵ and R⁶ together may form ═O.

In an exemplary iteration of this embodiment, R² is halogen. Preferably,the halogen is bromide or chloride.

(e) Exemplary Compounds

Non-limiting examples of exemplary compounds having formula (I), (Ia),(Ib), or (Ic) are presented in Table A.

TABLE A Compound No. Structure  8-1

 9-1

10-1

11-1

12-1

13-1

The compounds described above may have a (−) or (+) stereochemistryconfiguration, with respect to the rotation of polarized light. Morespecifically, each chiral center may have an R or an S configuration.

For ease of discussion, the ring atoms of the core morphinan structurereferenced herein are numbered as follows:

Carbons 13, 14, and 9 are chiral centers. Accordingly, the configurationof a compound of the invention having structure (I), (Ib), or (Ic) maybe RRS, RSS, SRR, or SSR, with respect to C13, C14, and C9. Likewise,the configuration of compounds 8-1 and 9-1 may be RRS, RSS, SRR, or SSR,with respect to C13, C14, and C9. In exemplary embodiments, theconfiguration of compounds 8-1 and 9-1 may be (−)RSS.

In sinomenine derivatives in which an ether-containing ring linkscarbons 4 and 5, there are four chiral carbons, i.e., carbons 5, 13, 14,and 9. Thus, the configuration of compounds of the invention havingformula (Ia) may be RRRS, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR, or SSSR,with respect to C5, C13, C14, and C9. Likewise, the configuration ofcompounds 10-1, 11-1, 12-1, and 13-1 may be RRRS, RRSS, SRRS, SRSS,RSRR, RSSR, SSRR, or SSSR, with respect to C5, C13, C14, and C9. Inexemplary embodiments, the configuration of compounds 10-1, 11-1, 12-1,and 13-1 may be (+)SRSS.

The invention also encompasses salts of any of the above-describedcompounds having Formula (I), (Ia), (Ib), and (Ic). Exemplary saltsinclude without limitation hydrochloride, hydrobromide, phosphate,sulfate, methansulfonate, acetate, formate, tartaric acid, maleic,malic, citrate, isocitrate, succinate, lactate, gluconate, glucuronate,pyruvate, oxalate, fumarate, propionate, aspartate, glutamate, benzoate,methyl fluoride, methyl chloride, methyl bromide, methyl iodide, and thelike.

(II) Processes for Preparing Sinomenine Derivatives

Another aspect of the invention provides processes for preparing thesinomenine derivatives having Formula (I), (Ia), (Ib), and (Ic) orintermediates that may be used in the production of sinomeninederivatives. While it is envisioned that the synthetic routes describedherein may be utilized to produce (+/−)-sinomenine derivatives, in anexemplary aspect of the invention, the process encompasses theproduction of (+)-sinomenine derivatives. For purposes of illustration,Reaction Scheme 1 depicts production of compound 7 in accordance withone aspect of the invention.

wherein:

R¹ is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl;

R² and R³ are independently selected from the group consisting ofhydrogen, halogen, OH, NH₂, CN, hydrocarbyl, and substitutedhydrocarbyl;

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, OH, NH₂, CN, hydrocarbyl, and substituted hydrocarbyl; whereinR⁴ and R⁵ together may form a group selected from the group consistingof ═O, ═NOH, ═S, ═CHR^(5a), and —O(CH₂)₂O—;

R^(5a) is selected from the group consisting of hydrogen, halogen,hydrocarbyl, and substituted hydrocarbyl;

R⁶ is selected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, OH, NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, whereinR⁷ and R⁸ together may form a group selected from the group consistingof ═O and ═S;

X is halogen;

Y is selected from the group consisting of alkyl, substituted alkyl,carbonyl, and alkyl carbonyl; and

Z is selected from the group consisting of oxygen, nitrogen and sulfur.

In an alternative of this embodiment, the constituents of the reactioncomprise:

R¹ is selected from the group consisting of an alkyl group having from 1to 8 carbon atoms, a vinyl group, an aryl group, cyclopropyl,cyclobutyl, {—}CH(CF₃)₂, {—}CH(CH₃)CF₃, {—}CH═CF₂, and {—}CH₂CF₃,

R² and R³ are independently selected from the group consisting ofhydrogen, halogen, OH, NH₂ CN, acyl, alkyl, alkenyl, aryl, alkoxyl, andalkylamino;

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, OH, and alkoxyl, wherein R⁴ and R⁵ together may form a groupselected from the group consisting of ═O, ═NOH, and —O(CH₂)₂O—;

R⁶ is selected from the group consisting of hydrogen and alkyl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, OH and NH₂, wherein R⁷ and R⁸ together may form ═O;

X is selected from the group consisting of bromide and chloride;

Y is selected from the group consisting of {—}CH₂{—} and {—}CO{—}; and

Z is oxygen.

In a further iteration of this alternative, R¹ is cyclopropyl; R² ishydrogen; R³ is {—}O(CH₂)_(m)CH₃; R⁴ and R⁵ together form ═O; R⁶, R⁷,and R⁸ are each hydrogen; and m is from 0 to 8. In an exemplaryiteration, X is bromide and m is 0.

(a) Step A: Conversion of Compound 2 to Compound 3

In Step A of the process, the substrate, compound 2, is contacted witheither vinyl chloroformate or 1-chloroethyl chloroformate, followed byhydrolysis of the reaction mixture in the presence of either a dilutesolution of a proton donor or a proton acceptor to form compound 3.

The reaction may be conducted in the presence of a solvent. The solventmay be an aprotic solvent. Non-limiting examples of aprotic solventsinclude ether solvents, acetone, acetonitrile, benzene, diethoxymethane,N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N-dimethylpropionamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME),dimethylacetamide (DMAC), N-methylpyrrolidinone (NMP), ethyl acetate,ethyl formate, ethyl methyl ketone, formamide, isobutylmethylketone,hexamethylphosphoramide, methyl acetate, N-methylacetamide,N-methylformamide, methylene chloride, nitrobenzene, nitromethane,propionitrile, sulfolane, tetramethylurea, tetrahydrofuran (THF),toluene, trichloromethane. In a preferred embodiment, the aproticsolvent may be dimethylformamide, dimethyl sulfoxide, dioxane,formamide, or N-methylacetamide.

The weight ratio of aprotic solvent to compound 2 may range from about1:1 to about 20:1. In one embodiment, the weight ratio of solvent tocompound 2 may range from about 1:1 to about 3:1. In another embodiment,the weight ratio of solvent to compound 2 may range from about 6:1 toabout 12:1. In still another embodiment, the weight ratio of solvent tocompound 2 may range from about 12:1 to about 20:1. In a preferredembodiment, the weight ratio of solvent to compound 2 may range fromabout 3:1 to about 6:1.

The reaction mixture is typically then treated with a dilute solution ofproton donor or proton acceptor to form compound 3. In general, theproton donor has a pKa less than about 6. Suitable proton donorsinclude, but are not limited to, HOAc, HCO₂H, H₂CO₃, MeSO₃H, poly H₃PO₄,H₃PO₄, H₂SO₄, HCl, HBr, HI, CF₃SO₃H, and p-methyltoluenesulfonic acid.The proton acceptor typically has a pKa between about 7 and about 13.Suitable proton acceptors having this characteristic include boratesalts (such as, for example, NaBO₃), di- and tri-basic phosphate salts(such as, for example, Na₂HPO₄ and Na₃PO₄, and the like), bicarbonatesalts (such as, for example, NaHCO₃, KHCO₃, LiCO₃, and the like),carbonate salts (such as, for example, Na₂CO₃, K₂CO₃, Li₂CO₃, and thelike), organic bases (such as, for example, pyridine, triethylamine,diisopropylethylamine, N-methylmorpholine, N,N-dimethylaminopyridine),and mixtures of any of the above. In a preferred embodiment, the protonacceptor may be NaHCO₃, KHCO₃, LiCO₃, Na₂CO₃, K₂CO₃, Li₂CO₃, or amixture thereof. In an exemplary embodiment, the proton acceptor may beNaHCO₃.

The amount of the reactants contacted with compound 2 can and will vary.Typically, the weight ratio of compound 2 to vinyl chloroformate or1-chloroethyl chloroformate to proton donor or proton acceptor may rangefrom about 1:2:1 to about 1:20:20. In one embodiment, the weight ratioof compound 2 to vinyl chloroformate or 1-chloroethyl chloroformate toproton donor or proton acceptor may range from about 1:2:1 to about1:4:4. In another embodiment, the weight ratio of compound 2 to vinylchloroformate or 1-chloroethyl chloroformate to proton donor or protonacceptor may range from about 1:4:4 to about 1:10:10. In still anotherembodiment, the weight ratio of compound 2 to vinyl chloroformate or1-chloroethyl chloroformate to proton donor or proton acceptor may rangefrom about 1:10:10 to about 1:20:20. In a preferred embodiment, theweight ratio of compound 2 to vinyl chloroformate or 1-chloroethylchloroformate to proton donor or proton acceptor may range from about1:3:3 to about 1:12:12.

The reaction may be conducted at a temperature that ranges from about50° C. to about 120° C. In one embodiment, the temperature of thereaction may range from about 100° C. to about 120° C. In an alternateembodiment, the temperature of the reaction may range from about 80° C.to about 100° C. In a preferred embodiment, the temperature of thereaction may range from about 50° C. to about 80° C. The reaction ispreferably performed under ambient pressure, and preferably in an inertatmosphere (e.g., nitrogen or argon).

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete, as determined by chromatography(e.g., HPLC). In this context, a “completed reaction” generally meansthat the reaction mixture contains a significantly diminished amount ofcompound 1 and a significantly increased amount of compound 2 comparedto the amounts of each present at the beginning of the reaction.

The yield of compound 3 may vary. Typically, the yield of compound 3 mayrange from about 40% to about 70%. In one embodiment, the yield ofcompound 3 may range from about 40% to about 50%. In another embodiment,the yield of compound 3 may range from about 50% to about 60%. In stillanother embodiment, the yield of compound 3 may range from about 60% toabout 70%.

(b) Step B: Conversion of Compound 3 to Compound 4

In Step B of the process, compound 3 is alkylated with R¹YX or undergoesreductive amination with R¹Y to form compound 4. R¹, Y, and X are asdefined above. Preferably, Y is —CH₂— or —CHO. The process comprisescontacting compound 3 with either R⁷YX or R⁷Y to form compound 4.

The reaction may be conducted in the presence of a solvent. The solventmay be an aprotic solvent. Suitable aprotic solvents are as described inStep A of the process. In general, the weight ratio of solvent tocompound 3 may range from about 1:1 to about 20:1. In one embodiment,the weight ratio of solvent to compound 3 may range from about 1:1 toabout 4:1. In an alternate embodiment, the weight ratio of solvent tocompound 3 may range from about 4:1 to about 20:1.

The amount of R¹YX or R¹Y contacted with compound 3 may vary. Ingeneral, the weight ratio of compound 3 to R¹YX or R¹Y may range fromabout 1:1 to about 1:3. In one embodiment, the weight ratio of compound3 to R¹YX or R¹Y may range from about 1:1 to about 1:2. In anotherembodiment, the weight ratio of compound 3 to R¹YX or R¹Y may range fromabout 1:2 to about 1:3. In a preferred embodiment, the weight ratio ofcompound 3 to R¹YX or R¹Y may range from about 1:1.1 to about 1:1.5.

The temperature of the reaction may range from about 20° C. to about100° C. In one embodiment, the temperature of the reaction may rangefrom about 20° C. to about 40° C. In another embodiment, the temperatureof the reaction may range from about 40° C. to about 70° C. In stillanother embodiment, the temperature of the reaction may range from about70° C. to about 100° C. The reaction is preferably performed underambient pressure, and preferably in an inert atmosphere (e.g., nitrogenor argon).

The reaction is typically allowed to proceed for a sufficient period oftime until the reaction is complete, as determined by a technique, suchas chromatography, well known in the art. In general, the yield ofcompound 4 may range from about 60% to about 80%. In one embodiment, theyield of compound 4 may range from about 60% to about 70%. In anotherembodiment, the yield of compound 4 may range from about 70% to about80%.

(c) Step C: Conversion of Compound 4 to Compound 5

In Step C of the process, compound 4 is contacted with X₂ to formcompound 5. X₂ is as defined above.

The reaction may be conducted in the presence of a solvent. The solventmay be an organic solvent. Suitable organic solvents include, but arenot limited to, alkane and substituted alkane solvents (includingcycloalkanes), aromatic hydrocarbons, esters, ethers, ketones,combinations thereof, and the like. Specific organic solvents that maybe employed, include, for example, acetonitrile, benzene, butyl acetate,t-butyl methylether, t-butyl methylketone, chlorobenzene, chloroform,chloromethane, cyclohexane, dichloromethane, dichloroethane, diethylether, ethyl acetate, fluorobenzene, heptane, hexanes,isobutylmethylketone, isopropyl acetate, methylethylketone,methyltetrahydrofuran, pentyl acetate, n-propyl acetate,tetrahydrofuran, toluene, combinations thereof, and the like. In apreferred embodiment, the organic solvent may be benzene, chloroform,diethyl ether, ethyl acetate, heptane, hexane, or toluene.

In general, the weight ratio of organic solvent to compound 4 may rangefrom about 5:1 to about 50:1. In one embodiment, the weight ratio oforganic solvent to compound 4 may range from about 5:1 to about 20:1. Inanother embodiment, the weight ratio of organic solvent to compound 4may range from about 20:1 to about 50:1.

Generally speaking, about 2 molar equivalents of X₂ are contacted withcompound 4. In one embodiment, the weight ratio of compound 4 to X₂ mayrange from about 1:2 to about 1:2.5. In a preferred embodiment, theweight ratio of compound 4 to X₂ may be about 1:2.1.

Optionally, in one embodiment, a base may be added to the reaction ofStep C. Generally, the base is a liquid at the temperature at which thereaction is conducted. For example, triethylamine is one such suitablebase. It is generally believed, without being bound by theory, that theaddition of a base to Step C may neutralize the acid formed (e.g.,hydrogen bromide when X is bromide) so that the acid is prevented fromreacting with reactants or products. In a further optional embodiment, ahalogen scavenger may be added. For example, when the halogen isbromine, a bromine scavenger such as 2,3-dimethyl-1,3-butadiene may beadded.

The temperature of the reaction may range from about −30° C. to about 0°C., and more preferably from about −20° C. to about −5° C. In oneembodiment, the temperature of the reaction may range from about −20° C.to about −10° C. In another embodiment, the temperature of the reactionmay range from about −10° C. to about −5° C. The reaction is preferablyperformed under ambient pressure, and preferably in an inert atmosphere(e.g., nitrogen or argon).

The reaction is typically allowed to proceed for a sufficient period oftime until the reaction is complete, as determined using standardtechniques. The yield of compound 5 may vary, depending upon thereaction conditions. In general, the yield of compound 5 may range fromabout 20% to about 70%. In one embodiment, the yield of compound 5 mayrange from about 20% to about 40%. In an alternate embodiment, the yieldof compound 5 may range from about 40% to about 60%. In anotheralternate embodiment, the yield of compound 5 may range from about 60%to about 70%.

(d) Step D: Conversion of Compound 5 to Compound 6

Step D of the process involves a ring closure reaction. The processcomprises contacting compound 5 with a proton acceptor to form compound6.

The reaction may be conducted in the presence of a solvent. The solventmay be an aprotic solvent, a protic solvent, or a mixture thereof.Suitable aprotic solvents are as described in Step A of the process.Non-limiting examples of suitable protic solvents include methanol,ethanol, isopropanol, n-propanol, isobutanol, t-butanol, n-butanol,formic acid, acetic acid, and water. In one embodiment, the solvent maybe an aprotic solvent or a combination thereof. In another embodiment,the solvent may be a protic solvent or a combination thereof. In stillanother embodiment, the solvent may be a solvent system in that itcomprises a combination of aprotic solvent(s) and protic solvent(s).

Typically, the weight ratio of solvent or solvent system to compound 5may range from about 5:1 to about 50:1. In one embodiment, the weightratio of solvent or solvent system to compound 5 may range from about5:1 to about 20:1. In another embodiment, the weight ratio of solvent orsolvent system to compound 5 may range from about 20:1 to about 50:1.

In general, the proton acceptor used in this step has a pKa greater thanabout 12. Non-limiting examples of suitable proton acceptors having thischaracteristic include hydroxides of alkali metals and alkaline earthmetals (such as, for example, NaOH and Ca(OH)₂ and the like), as well asgroup 1 salts of carbanions, amides, and hydrides (such as, for example,butyl lithium, sodium amide (NaNH₂), sodium hydride (NaH), and thelike). In a preferred embodiment, the proton acceptor may be NaOH, KOH,LiOH, Ca(OH)₂ or NaH. In an exemplary embodiment, the proton acceptormay be NaOH.

The amount of proton acceptor added to the reaction is generally enoughto keep the pH of the reaction mixture about 13 or higher. Typically,the weight ratio of compound 5 to proton acceptor may range from about1:1.5 to about 1:20. In one embodiment, the weight ratio of compound 5to proton acceptor may range from about 1:1.5 to about 1:5. In anotherembodiment, the weight ratio of compound 5 to proton acceptor may rangefrom about 1:5 to about 1:20.

The temperature of the reaction may range from about −30° C. to about 0°C., and more preferably from about −20° C. to about −5° C. In oneembodiment, the temperature of the reaction may range from about −20° C.to about −10° C. In another embodiment, the temperature of the reactionmay range from about −10° C. to about −5° C. The reaction is preferablyperformed under ambient pressure, and preferably in an inert atmosphere(e.g., nitrogen or argon).

The reaction is typically allowed to proceed for a sufficient period oftime until the reaction is complete, as determined using techniquesknown to those of skill in the art. The yield of compound 6 made fromcompound 5 may vary, depending upon the reaction conditions. In general,the yield of compound 6 may range from about 70% to about 95%. In oneembodiment, the yield of compound 6 may range from about 70% to about80%. In another embodiment, the yield of compound 6 may range from about80% to about 90%. In yet another embodiment, the yield of compound 6 mayrange from about 90% to about 95%.

(e) Step E: Conversion of Compound 6 to Compound 7

In Step E of the process, compound 6 is contacted with a scavenger and aproton donor to form compound 7.

The reaction may be conducted in the presence of a solvent. The solventmay be an aprotic solvent, as detailed above in Step A of the process.Typically, the weight ratio of solvent or solvent system to compound 6may range from about 5:1 to about 50:1. In one embodiment, the weightratio of solvent or solvent system to compound 6 may range from about5:1 to about 20:1. In another embodiment, the weight ratio of solvent orsolvent system to compound 6 may range from about 20:1 to about 50:1.

Typically, the scavenger is an alcohol scavenger. The alcohol may havefrom about one to about eight carbon atoms. In an exemplary embodiment,the alcohol scavenger is a methanol scavenger. Non-limiting examples ofsuitable alcohol scavengers include P₂O₅, POCl₃, POBr₃, PCl₃, SOCl₂,SOBr₂, MeSO₂Cl, (MeSO₂)₂O, SO₃, (CF₃SO₂)₂O, and (CF₃C0)₂O. In apreferred embodiment, the alcohol scavenger may be POCl₃.

The proton donor generally has a pKa less than about 0. Suitable protondonors having this characteristic include, but are not limited to,MeSO₃H, poly H₃PO₄, H₃PO₄, H₂SO₄, HCl, HBr, HClO₄, HI, HNO₃, CF₃SO₃H,p-methyltoluenesulfonic acid, HClO₃, HBrO₄, HIO₃, and HIO₄. In apreferred embodiment, the proton donor may be MeSO₃H, poly H₃PO₄, H₃PO₄,H₂SO₄, HCl, HBr, CF₃SO₃H, and p-methyltoluenesulfonic acid. In apreferred embodiment, the proton donor may be MeSO₃H.

In general, the weight ratio of compound 6 to scavenger to proton donoris from about 1:0.5:2 to about 1:2:20. In one embodiment, the weightratio of compound 6 to scavenger to proton donor is from about 1:0.5:2to about 1:1:5. In an alternate embodiment, the weight ratio of compound6 to scavenger to proton donor is from about 1:1:5 to about 1:2:20.

The temperature of the reaction may range from about 0° C. to about 100°C., and more preferably from about 20° C. to about 45° C. In oneembodiment, the temperature of the reaction may range from about 20° C.to about 35° C. In another embodiment, the temperature of the reactionmay range from about 35° C. to about 45° C. The reaction is preferablyperformed under ambient pressure, and preferably in an inert atmosphere(e.g., nitrogen or argon).

The reaction is typically allowed to proceed for a sufficient period oftime until the reaction is complete, as determined using standardtechniques. The yield of compound 7 generally will range from about 20%to about 60%. In one embodiment, the yield of compound 7 may range fromabout 20% to about 40%. In another embodiment, the yield of compound 7may range from about 40% to about 50%. In yet another embodiment, theyield of compound 7 may range from about 50% to about 60%.

(f) Preparation of Exemplary Compounds

Compound 7 and certain intermediate compounds, such as compounds 4 and6, depicted in Reaction Scheme 1 may be utilized to prepare one or moresinomenine derivative compounds having formula (I), (Ia), (Ib), or (Ic).By way of non-limiting example, compounds 4, 6, and 7 may be reduced toform compounds 8-1, 10-1, and 13-1, respectively. A variety of reducingapproaches may be employed including, for example, chemical reduction,catalytic reduction, and the like. Representative reducing agents foruse in chemical reduction include hydrides (e.g., hydrogen iodide,hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodiumcyanoborohydride, and the like), or combinations of a metal (e.g., tin,zinc, or iron) or a metal compound (e.g., chromium chloride, chromiumacetate, and the like) with an organic or inorganic acid (e.g., formicacid, acetic acid, propionic acid, trifluoroacetic acid,p-toluenesulfonic acid, hydrochloric acid, and the like), samariumiodide, and others. In an exemplary embodiment, the reducing agent maybe sodium borohydride (NaBH₄). Representative reducing agents for use incatalytic reduction methods with hydrogen include commonly usedcatalysts such as, for example, platinum catalysts (e.g., platinumblack, colloidal platinum, platinum oxide, platinum plate, platinumsponge, platinum wire, and the like), palladium catalysts (e.g.,palladium black, palladium on barium carbonate, palladium on bariumsulfate, colloidal palladium, palladium on carbon, palladium hydroxideon carbon, palladium oxide, palladium sponge, and the like), nickelcatalysts (e.g., nickel oxide, Raney nickel, reduced nickel, and thelike), cobalt catalysts (e.g., Raney cobalt, reduced cobalt, and thelike), iron catalysts (e.g., Raney iron, reduced iron, Ullmann iron, andthe like), and others. For the preparation of compounds 8-1 and 10-1, acombination of chemical and catalytic reduction may be required.

Furthermore, compounds 4-1 and 6-1 (see Reaction Scheme 2 in theExamples) may undergo reductive amination to form compounds 9-1 and11-1, respectively. Suitable reagents and conditions are generally knownin the art. As an example, reductive amination may be conducted in thepresence of hydrogen gas with a palladium, platinum, or nickelcatalysts, as defined above. Alternatively, the reductive amination maycomprise hydrogen and a Noyori catalyst, formic acid, and a tertiaryamine.

Additionally, compound 7-1 (see Reaction Scheme 2 in the Examples) mayundergo hydrogenation to form compound 12-1. The hydrogenation may becatalytic, that is in the presence of hydrogen and a metal catalyst, asdetailed above. Suitable metal catalysts include platinum, palladium,rhodium, ruthenium, and the like. One of skill in the art will befamiliar with reaction conditions and other variables.

DEFINITIONS

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxy group from the groupCOOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R₁, R₁O—,R₁R₂N—, or R₁S—, R₁ is hydrocarbyl, heterosubstituted hydrocarbyl, orheterocyclo, and R₂ is hydrogen, hydrocarbyl, or substitutedhydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group,denotes an acyl group as described above bonded through an oxygenlinkage (O), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

The term “alcohol scavenger” as used herein is a reagent that can reactwith an alcohol and release an acid at the same time.

The term “alkyl” as used herein describes groups which are preferablylower alkyl containing from one to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl,and the like.

The term “alkaryl” or “alkylaryl” as used herein describes groups whichare preferably aryl groups having a lower alkyl substituent, such astoluoyl, ethylphenyl, or methylnapthyl.

The term “alkenyl” as used herein describes groups which are preferablylower alkenyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. The may be straight or branched chainor cyclic and include ethenyl, propenyl, isopropenyl, butenyl,isobutenyl, hexenyl, and the like.

The term “alkynyl” as used herein describes groups which are preferablylower alkynyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainand include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and thelike.

The term “aralkyl” as used herein describes groups which are preferablylower alkyl containing from one to eight carbon atoms having an arylsubstituent, such as benzyl, phenylethyl, or 2-naptheylmethyl.

The term “aromatic” as used herein alone or as part of another groupdenotes optionally substituted homo- or heterocyclic aromatic groups.These aromatic groups are preferably monocyclic, bicyclic, or tricyclicgroups containing from 6 to 14 atoms in the ring portion. The term“aromatic” encompasses the “aryl” and “heteroaryl” groups defined below.

The term “aryl” as used herein alone or as part of another group denotesoptionally substituted homocyclic aromatic groups, preferably monocyclicor bicyclic groups containing from 6 to 12 carbons in the ring portion,such as phenyl, biphenyl, naphthyl, substituted phenyl, substitutedbiphenyl or substituted naphthyl. Phenyl and substituted phenyl are themore preferred aryl.

The terms “halogen” or “halo” as used herein alone or as part of anothergroup refer to chlorine, bromine, fluorine, and iodine.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or non-aromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to theremainder of the molecule through a carbon or heteroatom. Exemplaryheterocyclo groups include heteroaromatics as described below. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy,alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano,ketals, acetals, esters, and ethers.

The term “heteroaryl” as used herein alone or as part of another groupdenotes optionally substituted aromatic groups having at least oneheteroatom in at least one ring, and preferably 5 or 6 atoms in eachring. The heteroaryl group preferably has 1 or 2 oxygen atoms and/or 1to 4 nitrogen atoms in the ring, and is bonded to the remainder of themolecule through a carbon. Exemplary heteroaryls include furyl,benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl,imidazopyridyl, and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, hydroxy,protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy,halogen, amido, amino, cyano, ketals, acetals, esters, and ethers.

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with aheteroatom such as nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or a halogen atom. These substituents include halogen,heterocyclo, alkoxy, alkenoxy, aryloxy, hydroxy, protected hydroxy,acyl, acyloxy, nitro, amino, amido, nitro, cyano, ketals, acetals,esters, and ethers.

The term “hydroxy protecting group” as used herein denotes a groupcapable of protecting a free hydroxy group (“protected hydroxy”), which,subsequent to the reaction for which protection is employed, may beremoved without disturbing the remainder of the molecule.

When introducing elements of the present invention or the preferredembodiments thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising,” “including,” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

As various changes could be made in the above compounds, products andmethods without departing from the scope of the invention, it isintended that all matter contained in the above description and in theexamples given below, shall be interpreted as illustrative and not in alimiting sense.

EXAMPLES

The following examples illustrate various iterations of the invention.

Example 1 Preparation of Sinomenine Derivatives

A synthetic route for preparing derivatives of sinomenine is presentedbelow in Reaction Scheme 2.

Sinomenine may be converted to compound 2-1 by catalytic hydrogenation.That is, sinomenine may be contacted with H₂, Pd/C, at a hightemperature. Compound 2-1 may be contacted with either vinylchloroformate or 1-chloroethyl chloroformate in the presence of anaprotic solvent, and then hydrolyzed in a dilute solution of a weak acidor weak base, such as NaHCO₃, to form compound 3-1. Compound 3-1 may bealkylated with cyclopropylCH₂X (wherein X is a halogen) or may undergoreductive amination with cyclopropylCHO to form compound 4-1. Compound4-1 may be reacted with two equivalences of X to form compound 5-1. Astrong base (i.e., having a pKa>13), such as NaOH, may be added to theprevious reactive mixture to form compound 6-1. Compound 6-1 may bereacted with an alcohol scavenger, such as POCl₃, and a strong acid(i.e., having a pKa<0) to form compound 7-1.

Example 2 Bromination with TEA Addition

The addition of a base, such as triethylamine, that is liquid at lowtemperatures, to the bromination reaction at low temperatures, prior tothe aqueous sodium hydroxide quench, neutralizes the HBr produced in thereaction. This prevents this acid from reacting with the product as thereaction solution is warmed to temperatures at which it can be mixedwith aqueous sodium hydroxide. In one example, TEA may be added to thefollowing bromination Reaction 3:

3.0 g of Dihydrosinomenine were dissolved in 150 mL dichloromethane in a500 mL 3-neck flask. 0.12 mL meslic acid were added. The solution wascooled to −30° C. A solution of 1.02 mL Br₂ in 10 mL dichloromethane wasslowly added. For the first half of the bromine addition, the brominecolor disappeared rapidly. The solution was allowed to warm to −20° C.and the reaction was monitored by HPLC. When the peak for the mono-bromointermediate had finished decreasing, 3.79 mL of Triethylamine wereadded. The solution turned bright purple. The solution was then allowedto warm to 0° C. 54.3 mL of 1N Aq. NaOH were added. The reaction mixturewas transferred to a separation funnel. The two phases were separatedand the aqueous phase was extracted with dichloromethane twice more. Theorganic layers were combined, dried with magnesium sulfate, and strippedto a yellow solid (3.55 g) containing 14 area % Cmp, 2 and 44 area %Cmp. 3. The structures for Cmp. 2 and Cmp. 3 are supported by massspectrometry and NMR data.

Example 3 Bromination with TEA Addition and 2,3-dimethyl-1,3-butadieneAddition

The addition of a bromine scavenger, such as 2,3-dimethyl-1,3-butadiene,to the reaction illustrated in Reaction Scheme 3 before the aqueoussodium hydroxide quench removes excess bromine. This prevents the excessbromine from oxidizing the phenoxide compounds, formed when the aqueoussodium hydroxide is added, thus preventing the formation of highlycolored impurities.

3.0 g of Dihydrosinomenine were dissolved in 150 mL dichloromethane in a500 mL 3-neck flask. 0.12 mL meslic acid were added. The solution wascooled to −30° C. A solution of 1.02 mL Br₂ in 10 mL dichloromethane wasslowly added. For the first half of the bromine addition, the brominecolor disappeared rapidly. The solution was allowed to warm to −20° C.and the reaction was monitored by HPLC. When the peak for the mono-bromointermediate had finished decreasing, 2.78 mL of Triethylamine wereadded. The solution turned bright purple. Then 0.31 mL of2,3-dimethyl-1,3-butadiene were added. The color of the solutionlightened to brownish dark green. The solution was then allowed to warmto 0° C. 54.3 mL of 1N Aq. NaOH were added. The reaction mixture wastransferred to a separation funnel. The two phases were separated andthe aqueous phase was extracted with dichloromethane twice more. Theorganic layers were combined, dried with magnesium sulfate, and strippedto a yellow solid (3.39 g).

Example 4 Enrichment of Cmp. 2 by Extraction of Cmp. 3

Cmp. 2 and Cmp. 3 may be separated by extraction of a solution in anorganic solvent, such as toluene or a mixture of toluene and hexanes,with a basic aqueous solution. For example, 1.00 g of the product fromthe “Bromination with TEA addition and 2,3-dimethyl-1,3-butadieneaddition” example was dissolved in 150 mL toluene. This solution wasthen extracted with a solution of 50 mL concentrated ammonium hydroxideand 50 mL water. The toluene layer was then extracted with a solution of25 mL concentrated ammonium hydroxide and 75 mL water. The toluene layerwas then extracted with a solution of 15 mL concentrated ammoniumhydroxide and 85 mL water. The three aqueous extraction layers werecombined. HPLC analysis showed the preferential extraction of Cmp. 3into the aqueous layers. The toluene layer was again extracted threetimes as above. HPLC analysis showed only negligible amounts of Cmp. 3in the aqueous layers. 20 mL of toluene were stripped under vacuum fromthe toluene layer. 50 mL of hexanes were added. This organic solutionwas extracted as above. HPLC analysis showed the preferential extractionof Cmp. 3 into the aqueous layers. The organic layer was dried withmagnesium sulfate and stripped to 0.35 g of a brown oil containing 23area % Cmp. 2 and 15 area % Cmp. 3. The aqueous layers from the firstand third series of extractions were combined. Excess amounts of ammoniawere stripped off under vacuum. The aqueous solution was then extractedthree times with dichloromethane. The dichloromethane layers werecombined, dried with magnesium sulfate, and stripped to 0.23 g of gummysolids containing mostly Cmp. 3.

Example 5 Preparation of 1-Bromo-Dihydrosinomenine

Dihydrosinomenine may be mono-brominated to 1-bromo-dihydrosinomenine(Cmp. 4) according to Reaction Scheme 4:

3.0 g of Dihydrosinomenine were dissolved in 150 mL dichloromethane in a500 mL 3-neck flask. 0.12 mL meslic acid were added. The solution wascooled to −30° C. A solution of 0.44 mL Br₂ in 10 mL dichloromethane wasslowly added. The bromine color disappeared rapidly. The solution wasallowed to warm to −20° C. and the reaction was stirred for 15 minutes.The solution was then allowed to warm to 0° C. 10.4 mL of 1N Aq. NaOHwere added. The reaction mixture was transferred to a separation funnel.The two phases were separated and the aqueous phase was extracted withdichloromethane twice more. The organic layers were combined, dried withmagnesium sulfate, and stripped to a yellow solid (3.29 g) containing 90area % Cmp. 4. The structure for Cmp. 4 is supported by massspectrometry and NMR data.

Example 6 Preparation of 1-Bromo-7-Methoxylcodone

The compound may be prepared according to Reaction Scheme 5:

The solution of dihydrosinominene (1.0 g, 3.02 mmol, 1.0 eqv) in 30 mLacetonitrile was cooled to ˜−20° C. for 10 min. To the cooled solutionwas added methanesulfonic acid (1.1 mL, 17 mmol, 5.6 eqv). The reactionmixture turned clear solution. After stirring the reaction at −20° C.for five minutes, a solution of bromine (0.65 mL, 12.7 mmol, 4.2 eqv) in6 mL acetonitrile was added dropwise. The reaction turned light brownsolution. When the bath temperature was gradually raised to 0° C., thebath was switched to ice bath and kept the reaction stirring in ice bathfor one hr; then the reaction was quenched by adding 1.2 g powder KOH;the reaction was gradually warmed to room temperature overnight. Thereaction mixture was filtered, the solid was washed with acetonitrile(3×20 mL); the filtrate and washings were combined and evaporated; theresidue was dissolved in a mixture of 30 mL 1.0 N NaOH and 150 ml of 1:9DCM/EtOAc, the organic phase was washed with 1.0 N NaOH (5×40 mL),followed by washing with sodium metasulfate solution once, dried overanhydrous magnesium sulfate. After removing the volatiles, it gave anoff white solid, 0.55 g, purity=84%, yield=45%. LC-MS: M+1=406.10.

Example 7 Synthesis of 1-Bromo-7-Methoxylcodone 2

With reference to Reaction Scheme 5, the solution of dihydrosinominene(5.0 g, 15 mmol, 1.0 eqv) in 150 mL acetonitrile was cooled to ˜−1-20°C. for 10 min. To the cooled solution was added methanesulfonic acid(5.5 mL, 84.8 mmol, 5.7 eqv). The reaction mixture turned clearsolution. After stirring the reaction at −20° C. for five minutes, asolution of bromine (2.5 mL, 48.6 mmol, 3.2 eqv) in 30 mL acetonitrilewas added dropwise. The reaction turned light brown solution. When thebath temperature was gradually raised to 0° C., the bath was switched toice bath and kept the reaction stirring in ice bath for one hr; then thereaction was quenched by adding 6 g powder KOH; the reaction becamesolidified as a white chunk solid; to the reaction was added 200 mLacetonitrile. The resulting mixture was filtered and the solid waswashed with acetronitrile (3×30 mL); the filtrate and washings werecombined and evaporated to an oil. The oil residue was dissolved in 120mL of ethyl acetate; the resulting solution was washed with 1N NaOHsolution (5×80 mL) and dried over anhydrous magnesium sulfate. Afterremoving the volatiles, it gave 2.3 g white solid, yield=38% withpurity=85%.

Example 8 Synthesis of 1-Bromo-7-Methoxylhydrocodone 3

With reference to Reaction Scheme 5, dissolving 200 mg1-bromo-7-methoxycodone in 10 mL of KH₂PO₄/K₂HPO₄ buffer with pH=7. Theresulting solution was hydrogenised under 60 psi Hydrogen in thepresence of Wilkinson Catalyst at 35° C. overnight. After cooling toroom temperature, the volatiles were removed. It gave a brown mixturecontaining the desired product. LC-MS: M+1=408.14.

What is claimed is:
 1. A compound having Formula (I):

wherein: R¹ is selected from the group consisting of hydrocarbyl andsubstituted hydrocarbyl; R² is halogen; R³ is selected from the groupconsisting of hydrogen, halogen, OH, NH₂, CN, hydrocarbyl, andsubstituted hydrocarbyl; R⁴ is OR^(4a); R^(4a) is a bond that forms parkof an ether-containing ring; R⁵ and R⁶ are independently selected fromthe group consisting of hydrogen, OH, NH₂, SH, hydrocarbyl, andsubstituted hydrocarbyl, wherein R⁵ and R⁶ together may form a groupselected from the group consisting of ═O, ═NOH, ═S, ═CHR^(5a), and—O(CH₂)₂O—; R^(5a) is selected from the group consisting of hydrogen,halogen, hydrocarbyl, and substituted hydrocarbyl; R⁷ is OR^(7a); R^(7a)is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl; R⁸ is selected from the group consisting of hydrogen,hydrocarbyl, and substituted hydrocarbyl; R⁹ and R¹⁰ are independentlyselected from the group consisting of hydrogen, OH, NH₂, SH,hydrocarbyl, and substituted hydrocarbyl, wherein R⁹ and R¹⁰ togethermay form a group selected from the group consisting of ═O and ═S; R¹¹and R¹² are independently selected from the group consisting ofhydrogen, OH, halogen, hydrocarbyl, and substituted hydrocarbyl; Y isselected from the group consisting of alkyl, substituted alkyl,carbonyl, and alkyl carbonyl; m is an integer from 0 to 8; and ----- isa single bond or a double bond, and further wherein C9, C13 and C14reference carbon numbers 9, 13 and 14, respectively, of Formula (I). 2.The compound of claim 1, wherein: R¹ is selected from the groupconsisting of an alkyl group having from 1 to 8 carbon atoms, a vinylgroup, an aryl group, cyclopropyl, cyclobutyl, {—}CH(CF₃)₂,{—}CH(CH₃)CF₃, {—}CH═CF₂, and {—}CH₂CF₃; R² is halogen; R⁵ and R⁶ areindependently selected from the group consisting of hydrogen, OH, andNH₂, wherein R⁵ and R⁶ together may form ═O; R³ and R⁸-R¹² are eachhydrogen; Y is selected from the group consisting of {—}CH₂{—} and{—}CO{—}; and m is
 0. 3. The compound of claim 1, wherein the compoundhas Formula (Ia):

wherein: R² is halogen; R⁵ and R⁶ are independently selected from thegroup consisting of hydrogen, OH, NH₂, SH, hydrocarbyl, and substitutedhydrocarbyl, wherein R⁵ and R⁶ together may form a group selected fromthe group consisting of ═O, ═NOH, ═S, ═CHR^(5a), and —O(CH₂)₂O—; R^(5a)is selected from the group consisting of hydrogen, halogen, hydrocarbyl,and substituted hydrocarbyl; R⁷ is OR^(7a); R^(7a) is selected from thegroup consisting of hydrocarbyl and substituted hydrocarbyl; R⁸ isselected from the group consisting of hydrogen, hydrocarbyl, andsubstituted hydrocarbyl; R⁹ and R¹⁰ are independently selected from thegroup consisting of hydrogen, OH, NH₂, SH, hydrocarbyl, and substitutedhydrocarbyl, wherein R⁹ and R¹⁰ together may form a group selected fromthe group consisting of ═O and ═S; Z is {—}O{—}; and ----- is a singlebond or a double bond.
 4. The compound of claim 1, wherein the compoundhas Formula (Ib):

wherein: R² is halogen; R⁴ is OR^(4a); R^(4a) is a bond that forms partof an ether-containing ring; R⁵ and R⁶ are independently selected fromthe group consisting of hydrogen, OH, NH₂, SH, hydrocarbyl, andsubstituted hydrocarbyl, wherein R⁵ and R⁶ together may form a groupselected from the group consisting of ═O, ═NOH, ═S, ═CHR^(5a), and—O(CH₂)₂O—; R^(5a) is selected from the group consisting of hydrogen,halogen, hydrocarbyl, and substituted hydrocarbyl; R⁷ is OR^(7a); R^(7a)is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl; and ----- is a single bond or a double bond.
 5. Thecompound of claim 1, wherein the compound is selected from the groupconsisting of:

wherein X is halogen.
 6. The compound of claim 1, wherein the opticalactivity of the compound is (−) or (+) and the configuration of C13,C14, and C9, respectively, is selected from the group consisting of RRS,RSS, SRR, and SSR.
 7. A process for preparing a compound of Formula (I)of claim 1, the process comprising contacting a compound having Formula5a with a proton acceptor to form a compound of Formula (I) according tothe reaction scheme:

wherein R¹ is selected from the group consisting of hydrocarbyl andsubstituted hydrocarbyl; R² is halogen; R³ is selected from the groupconsisting of hydrogen, halogen, OH, NH₂, CN, hydrocarbyl, andsubstituted hydrocarbyl; R⁴ is OH; R⁹ and R¹⁰ are independently selectedfrom the group consisting of hydrogen, OH, NH₂, SH, hydrocarbyl, andsubstituted hydrocarbyl, wherein R⁹ and R¹⁰ together may form a groupselected from the group consisting of ═O and ═S; and X is halogen; Y isselected from the group consisting of alkyl, substituted alkyl,carbonyl, and alkyl carbonyl; m is an integer from 0 to 8; and Z is{—}O{—}, and further wherein C5, C9, C13 and C14 reference carbonnumbers 5, 9, 13 and 14, respectively, of the compound of Formula (I).8. The process of claim 7, wherein the reaction is conducted in thepresence of an aprotic solvent; the weight ratio of solvent to compound5a is from about 5:1 to about 50:1; the proton acceptor has a pKagreater than about 13; the weight ratio of compound 5a to protonacceptor is from about 1:1.5 to about 1:20; the reaction is conducted ata temperature ranging from about −30° C. to about 0° C.; and the opticalactivity of compounds 5a and (I) is (−) or (+), and the configuration ofC5, C13, C14, and C9, respectively, is selected from the groupconsisting of RRRS, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR, and SSSR.
 9. Acompound having Formula (Ic):

wherein: R² is halogen; R⁴ is OR^(4a); R^(4a) is a bond that forms partof an ether-containing ring; R⁵ and R⁶ are independently selected fromthe group consisting of hydrogen, OH, NH₂, SH, hydrocarbyl, andsubstituted hydrocarbyl, wherein R⁵ and R⁶ together may form a groupselected from the group consisting of ═O, ═NOH, ═S, ═CHR^(5a), and—O(CH₂)₂O—; and R^(5a) is selected from the group consisting ofhydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl.
 10. Aprocess for preparing a compound of Formula (Ic) of claim 9, the processcomprising contacting a compound having Formula 6a with a scavenger anda proton donor to form the compound of Formula (Ic) according to thereaction scheme:

wherein R¹ is selected from the group consisting of hydrogen, halogen,OH, NH₂, CN, hydrocarbyl, and substituted hydrocarbyl; R² is halogen; R⁷is selected from the group consisting of hydrocarbyl and substitutedhydrocarbyl; R⁸ and R⁹ are independently selected from the groupconsisting of hydrogen, OH, NH₂, SH, hydrocarbyl, and substitutedhydrocarbyl, wherein R⁸ and R⁹ together may form a group selected fromthe group consisting of ═O and ═S; Y is selected from the groupconsisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl; mis an integer from 0 to 8; and Z is {—}O{—}, and further wherein C5, C9,C13 and C14 reference carbon numbers 5, 9, 13 and 14, respectively, ofthe compounds of Formulas 6 and (Ic).
 11. The process of claim 10,wherein the reaction is conducted in the presence of an aprotic solvent;the weight ratio of solvent to compound 6a is from about 5:1 to about50:1; the scavenger is an alcohol scavenger; the proton donor has a pKaless than about 0; the weight ratio of compound 6a to scavenger toproton donor is from about 1:0.5:2 to about 1:2:20; the reaction isconducted at a temperature ranging from about 0° C. to about 100° C.;and the optical activity of compounds 6a and (Ic) is (−) or (+), and theconfiguration of C5, C13, C14, and C9, respectively, is selected fromthe group consisting of RRRS, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR, andSSSR.
 12. A process for preparation of a compound of Formula (Ic) ofclaim 9 according to the following reaction scheme:

wherein: R¹ is selected from the group consisting of hydrocarbyl andsubstituted hydrocarbyl; R² and R³ are independently selected from thegroup consisting of hydrogen, halogen, OH, NH₂, CN, hydrocarbyl, andsubstituted hydrocarbyl; R⁴ is selected from the group consisting ofhydrogen, hydrocarbyl, and substituted hydrocarbyl; R⁵ and R⁶ areindependently selected from the group consisting of hydrogen, OH, NH₂,SH, hydrocarbyl, and substituted hydrocarbyl, wherein R⁵ and R⁶ togethermay form a group selected from the group consisting of ═O, ═NOH, ═S,═CHR^(5a), and —O(CH₂)₂O—; R^(5a) is selected from the group consistingof hydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl; R⁷ andR⁸ are independently selected from the group consisting of hydrogen, OH,NH₂, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R⁷ and R⁸together may form a group selected from the group consisting of ═O and═S; X is halogen; Y is selected from the group consisting of alkyl,substituted alkyl, carbonyl, and alkyl carbonyl; and Z is {—}O{—}, andfurther wherein C9, C13 and C14 reference carbon numbers 9, 13 and 14,respectively, of Formulas 2, 3, 4, 5, 6, and (Ic), and C5 referencescarbon number 5 of Formulas 6 and (Ic).
 13. The process of claim 12,wherein: R¹ is selected from the group consisting of an alkyl grouphaving from 1 to 8 carbon atoms, a vinyl group, an aryl group,cyclopropyl, cyclobutyl, {—}CH(CF₃)₂, {—}CH(CH₃)CF₃, {—}CH═CF₂, and{—}CH₂CF₃; R² and R³ are independently selected from the groupconsisting of hydrogen, halogen, OH, NH₂, CN, acyl, an alkyl, alkenyl,aryl, alkoxyl, and alkylamino; R⁴ is selected from the group consistingof hydrogen and alkyl; R⁵ and R⁶ are independently selected from thegroup consisting of hydrogen, OH, and alkoxyl, wherein R⁵ and R⁶together may form a group selected from the group consisting of ═O,═NOH, and —O(CH₂)₂O—; R⁷ and R⁸ are independently selected from thegroup consisting of hydrogen, OH and NH₂, wherein R⁷ and R⁸ together mayform ═O; X is selected from the group consisting of bromide andchloride; Y is selected from the group consisting of {—}CH₂{—} and{—}CO{—}; and Z is {—}O{—}.
 14. The process of claim 13, wherein: R¹ iscyclopropyl; R² is hydrogen; R³ is {—}O(CH₂)_(m)CH₃; R⁵ and R⁶ togetherform ═O; R⁴, R⁷, and R⁸ are each hydrogen; and m is an integer from 0 to8.
 15. The process of claim 12, wherein the weight ratio of compound 2to vinyl chloroformate or 1-chloroethyl chloroformate to proton acceptoror proton donor is from about 1:2:1 to about 1:20:20, the reaction ofStep A is conducted in the presence of an aprotic solvent, and at atemperature ranging from about 50° C. to about 120° C.; the weight ratioof compound 3 to R¹YX or R¹Y is from about 1:1 to about 1:3, thereaction of Step B is conducted in the presence of an aprotic solvent,and at a temperature ranging from about 20° C. to about 100° C.; theweight ratio of compound 4 to X₂ is from about 1:2 to about 1:2.5, thereaction of Step C is conducted in the presence of an organic solvent,and at a temperature ranging from about −30° C. to about 0° C.; theweight ratio of compound 5 to proton acceptor is from about 1:1.5 toabout 1:20, the reaction of Step D is conducted in the presence of anaprotic and/or a protic solvent, and at a temperature ranging from about−30° C. to about 0° C.; and the weight ratio of compound 6 to scavengerto proton donor is from about 1:0.5:2 to about 1:2:20, the reaction ofStep E is conducted in the presence of an aprotic solvent, and at atemperature ranging from about 0° C. to about 100° C.
 16. The process ofclaim 15, wherein the proton acceptor has a pKa greater than about 13and is selected from the group consisting of NaOH, KOH, LiOH, Ca(OH)₂,and NaH; the scavenger is an alcohol scavenger selected from the groupconsisting of P₂O₅, POCl₃, POBr₃, PCl₃, PBr₃, SOCl₂, SOBr₂, MeSO₂Cl,(MeSO₂)₂O, SO₃, (CF₃SO₂)₂O, and (CF₃CO)₂O; and the proton acceptor has apKa less than about 0 and is selected from the group consisting ofMeSO₃H, poly H₃PO₄, H₃PO₄, H₂SO₄, HCl, HBr, HlO₄, HNO₃, CF₃SO₃H, andp-methyltoluenesulfonic acid.
 17. The process of claim 12, wherein theoptical activity of compounds 2, 3, 4 and 5 is (−) or (+), and theconfiguration of C13, C14, and C9, respectively, is selected from thegroup consisting of RRS, RSS, SRR, and SSR.
 18. The process of claim 12,wherein the optical activity of compounds 6 and (Ic) is (−) or (+), andthe configuration of C5, C13, C14, and C9, respectively, is selectedfrom the group consisting of RRRS, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR,and SSSR.
 19. The compound of claim 9, wherein R⁵ and R⁶ together form═O.
 20. The compound of claim 9, wherein R⁵ is OH.
 21. The compound ofclaim 9, wherein R⁵ is NH₂.